Signaling Pathways that Impact Pathological Angiogenesis
Angiogenesis, the forming of new blood vessels, is a developmental process that can be recapitulated at any time in the life of a mammal.  Often this process proceeds normally, such as during organ growth or wound healing.  However, aberrant angiogenesis is an underlying contributor to many of our most debilitating diseases.  We are investigating the signaling pathways and key molecules that participate in a normal angiogenic response in a variety of diseases to understand how this process goes awry.    Projects include:

1) A study of sustained Akt signaling in vascular tumors and breast cancer progression.  Akt is an important mediator of cytokine signaling during angiogenesis.  In normal settings this process is highly regulated and transient. Dysregulated signaling can occur following mutation of negative regulators (e.g. PTEN) or cytokine receptors (e.g. Tie-2).  In addition, tumors that chronically produce high levels of cytokines chronically activate this pathway in endothelial cells.  We have created a model system to chronically activate Akt signaling only in endothelial cells and found that the blood vessels in this model resemble tumor blood vessels in both structure and function in the absence of tumor cells. Moreover, with time these vessels form vascular tumors reminiscent of hemangiomas.  The future direction of this project is to elucidate the downstream pathways that contribute to the altered structure and function, and investigate the role of endothelial cell Akt activation in tumor growth and metastasis.

2) RhoB modulation of endothelial cell signaling.  We have identified a novel regulator of  endothelial cell signaling.  The small GTPase, RhoB, modulates Akt signaling, VEGF signaling and we have evidence to suggest it may also regulate insulin signaling. Our ongoing investigation of RhoB function has focused on its role in retinal angiogenesis and retinopathy and is being extended to diabetic microvascular disease, including diabetic retinopathy.  We think of RhoB as a signaling modifier whose expression can determine whether an angiogenic response is ‘normal’ or pathological, and may be an appropriate drug target for the treatment of retinopathy.  We are also exploring the relationship of RhoB polymorphisms in the human population to diabetic microvascular complications.

3)  Endothelial Cell EMT.  Endocardial cells undergo a transition to mesenchymal cells during valve formation in the embryo.  We are investigating the role of RhoB regulation of Akt in this transition and their interactions with other known signaling pathways that participate in the EMT.  We think this process may bear on RhoB regulation of carcinoma progression in epithelial cells also.

 

References:

 

1.  Benjamin LE, Keshet E.  Conditional switching of vascular endothelial growth factor (VEGF) expression in tumors:  Induction of endothelial cell shedding and regression of hemangioblastoma-like vessels by VEGF withdrawal. Proc Natl Acad Sci 1997; 94:8761-6.
   
   
2. Benjamin LE, Hemo I. Keshet E.  A plasticity window for blood vessel remodelling is defined by pericyte coverage of the pre-formed endothelial network and regulated by PDGFB and VEGF.  Development 1998; 125:1591-8.
   
   
3. Jain RK, Safabakhsh N, Sckell A, Chen Y, Jiang P, Benjamin LE, Yuan Y, Keshet E. Endothelial cell death, angiogenesis, and microvascular function after castration in an androgen-dependent tumor: Role of vascular endothelial growth factor. Proc Natl Acad Sci 1998; 95: 10820-5.
   
   
4. Benjamin LE, Golijanin D, Itin A, Pode D, Keshet, E.  Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal. J Clin Invest 1999; 103:159-65.
   
   
5. Abramovitch, R., Dafni, H., Smouha,E., Benjamin, LE, and Neeman, M. In vivo visualization of vascular function, maturation and susceptibility to VEGF withdrawal:  MRI of C6 rat glioma in nude mice.  Can.Res1999; 59 (19) 5012-6.
   
   
6. Gross DJ, Reibstein I, Weiss L, Slavin S, Stein I, Neeman M, Abramovitch, R, Benjamin LE.  The anti-angiogenic agent linomide inhibits the growth rate of von Hippel-Lindau paraganglioma xenografts to mice. Clin. Canc.Res.1999;5(11):3669-75.
   
   
7. Adini A, Kornaga T, Firoozhbakht F, and Benjamin, L.E.  Placental Growth Factor provides survival functions for tumor endothelial cells and macrophages.  Cancer Res.  2002 May; 62(10): 2749-53.
   
   
8. Dafni, H., Israely, T., Bhujwalla, Z. M., Benjamin, L. E., and Neeman, M. Overexpression of vascular endothelial growth factor 165 drives peritumor interstitial convection and induces lymphatic drain: magnetic resonance imaging, confocal microscopy, and histological tracking of triple-labeled albumin. Cancer Res. 2002 62, 6731-6739.
   
   
9. Nagy, J. A., Vasile, E., Feng, D., Sundberg, C., Brown, L. F., Detmar, M. J., Lawitts, J. A., Benjamin, L.E., Tan, X., Manseau, E. J., et al. Vascular Permeability Factor/Vascular Endothelial Growth Factor Induces Lymphangiogenesis as well as Angiogenesis.  J Exp Med. 2002. 196, 1497-1506.
   
   
10. Sussman LK, Upalakalin JN, Roberts MJ, Kocher O, Benjamin L.E.  Blood markers for vasculogenesis increase with tumor progression in patients with breast carcinoma. Cancer Biol Ther. 2003 May-Jun;2(3):255-6.
    
    
11. Adini I, Rabinowitz I,Sun JF, Prendergast GP, and Benjamin L.E.  RhoB regulates Akt trafficking and stage-specific endothelial cell survival during vascular development.  Genes Dev. 2003 17: 2721-2732
    
    
12. Niu Q, Perruzzi C, Voskas D, Lawler J, Dumont D and  Benjamin L.E.  Inhibition of Tie-2 signaling induces endothelial cell apoptosis, decreases Akt signaling, and induces endothelial cell expression of the endogenous anti-angiogenic molecule, thrombospondin-1.  Cancer Biol & Ther. 2004. 3-4
    
    
13. Sun JF, Phung T, Shiojima I, Felske T, Feng D, Kornaga T, Dor T, Adini, I. Dvorak AM,, Walsh K, and Benjamin L.E.  Microvascular patterning is  controlled by fine-tuning the Akt signal.  Track II, PNAS 2005. Jan 4;102(1):128-33